ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.797C>T (p.Pro266Leu) (rs769420)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000121625 SCV000170636 benign not specified 2014-02-05 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000129165 SCV000183897 benign Hereditary cancer-predisposing syndrome 2014-12-12 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae RCV001082237 SCV000261615 benign Microcephaly, normal intelligence and immunodeficiency 2020-12-04 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000425619 SCV000511715 benign not provided 2016-12-30 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000121625 SCV000601702 benign not specified 2016-09-08 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129165 SCV000685826 benign Hereditary cancer-predisposing syndrome 2014-11-25 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000121625 SCV000806453 benign not specified 2017-10-11 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000425619 SCV000889557 benign not provided 2016-09-08 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001082237 SCV001321726 benign Microcephaly, normal intelligence and immunodeficiency 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286138 SCV001472667 benign none provided 2019-10-11 criteria provided, single submitter clinical testing
ITMI RCV000121625 SCV000085823 not provided not specified 2013-09-19 no assertion provided reference population
True Health Diagnostics RCV000129165 SCV000788082 likely benign Hereditary cancer-predisposing syndrome 2018-02-20 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000121625 SCV001553095 benign not specified no assertion criteria provided clinical testing The NBN p.Pro266Leu variant was identified in 14 of 2874 proband chromosomes (frequency: 0.005) from individuals or families with various types of cancer and was present in 4 of 1362 control chromosomes (frequency: 0.003) from healthy individuals (Berg 2013, Bodian 2014, Desjardins 2009, Yurgelun 2015). The variant was also identified in the following databases: dbSNP (ID: rs769420) as "With Benign allele", ClinVar (5x benign), Clinvitae (4x benign), and the Zhejiang Colon Cancer Database (1x). The variant was not identified in Cosmic or the LOVD 3.0 database. The variant was identified in control databases in 771 of 276952 chromosomes (11 homozygous) at a frequency of 0.003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 705 of 24006 chromosomes (freq: 0.03), Other in 5 of 6454 chromosomes (freq: 0.0008), Latino in 44 of 34382 chromosomes (freq: 0.001), European in 4 of 126556 chromosomes (freq: 0.00003), East Asian in 9 of 18864 chromosomes (freq: 0.0005), and South Asian in 4 of 30776 chromosomes (freq: 0.0001). The variant was not observed in the Ashkenazi Jewish or Finnish populations. Various studies utilizing computational algorithms, personal disease history, and family disease history have been performed; most of these studies conclude the variant is not associated with cancer (Berg 2013, Berardinelli 2013, Bodian 2014, Desjardins 2009, Gao 2013, Yurgelun 2015). The p.Pro266 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the leucine variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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